The role of Vpu-mediated tetherin antagonism in HIV-1 fitness

Abstract

HIV-1 groups M, N, O, and P resulted from four independent zoonotic transmission events of simian immunodeficiency viruses (SIV) infecting chimpanzees and gorillas to humans. Studying the differences between pandemic HIV-1 group M and closely related but less successful pathogens helps to expose viral vulnerabilities, which can be exploited as targets of new treatment or preventive strategies. One characteristic that distinguishes HIV-1 group M strains from the geographically-limited and less prevalent groups N, O and P is the acquisition of adaptive mutations in the accessory protein Vpu that mediate potent activity against human tetherin. This adaptation is thought to be critical for the effective spread of HIV-1 M strains within the human population because human tetherin harbours a deletion that renders it resistant to the counteraction by its SIV precursor. However, direct evidence supporting this hypothesis has been very limited. To address this issue and determine the contribution of Vpu-mediated tetherin counteraction to viral fitness, I mutated the AxxxA transmembrane domain Vpu motif of primary HIV-1 group M and N strains to specifically disrupt their ability to antagonize tetherin, but not other Vpu functions, such as downmodulation of CD4, CD1d and NTB-A, and suppression of NF-κB activity. Reversion of this particular human-specific adaptation significantly reduced the ability of HIV-1 group M Vpu proteins to enhance virus production and release from primary CD4+ T cells in the presence of type I interferon (IFN) by about 2- to 5-fold. These consistent differences between wild type and tetherin-defective mutant HIV-1 group M viruses highlight the important role of Vpu-mediated tetherin antagonism in viral release and resistance to IFN. Surprisingly, transmitted founder (TF) HIV-1 strains exhibited higher virion release capacity than chronic control HIV-1 strains irrespective of Vpu function. In addition, all pandemic group M viruses produced higher levels of cell-free virions than the poorly-adapted HIV-1 N group strain. In agreement with these in vitro data showing that Vpu-mediated tetherin antagonism plays an important role in HIV-1 fitness, the anti-tetherin activity was found to be critical for an efficient early spread of HIV-1 in humanized mice as shown in a study performed by our collaborator. Thus, efficient virus release from infected cells seems to play an important role in the spread of pandemic HIV-1 and requires a Vpu protein that efficiently counteracts human tetherin.